Pharmaceutical formulations containing dopamine receptor ligands

ABSTRACT

The present invention relates to stable and bioavailable immediate release formulations comprising dopamine receptor ligands. Methods of treating various disorders by administering the formulations are also described.

REFERENCE TO RELATED APPLICATIONS

This is a reissue application of U.S. application Ser. No. 12/504,149,filed Jul. 16, 2009, which issued as U.S. Pat. No. 9,056,845 on Jun. 16,2015, and which application claims the benefit of U.S. ProvisionalApplication No. 61/081,052, filed Jul. 16, 2008, all of which is areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to stable and bioavailable immediaterelease formulations comprising dopamine receptor ligands. Methods oftreating various disorders by administering the formulations are alsodescribed.

BACKGROUND OF THE INVENTION

Solid oral drug compositions or preparations have various releaseprofiles such as an immediate release profile as referenced by FDAguidelines (“Dissolution Testing of Immediate Release Solid Oral DosageForms”, issued August 1997, Section IV-A) or an extended release profileas referenced by FDA Guidelines (“Extended Release Oral Dosage Forms:Development, Evaluation, and Application of In Vitro/In VivoCorrelations”, Food and Drug Administration, CDER, September 1997, Page17). In the dissolution testing guideline for immediate releaseprofiles, materials which dissolve at least 80% in the first 30 to 60minutes in solution qualify as immediate release profiles. Therefore,immediate release solid dosage forms permit the release of most or allof the active ingredient over a short period of time, such as 60 minutesor less, and make rapid absorption of the drug possible.

Additional advantages of immediate release formulations includeincreased flexibility in drug administration by allowing the target drugto be administered either as multiples of lower strength formulations oras one higher strength formulation.

Food and Drug Administration guidelines (see, e.g., ICH Guideline Q3B,Revision 2, July 2006) provide limits for the amount of degradationproduct(s) that may be present in pharmaceutical formulations.

Maximum Daily Dose Degradation Product Threshold <10 mg 1.0% or 50 μgTDI, whichever is lower 10 mg-100 mg 0.5% or 200 μg TDI, whichever islower >100 mg-2 g 0.2% or 3 mg TDI, whichever is lower TDI: Total dailyintake

If the amount of degradation products exceeds the above thresholds,additional safety and toxicity studies may be required in accordancewith the guidelines. To avoid the need for additional testing, it istherefore important to develop dosage forms that are stable overextended periods of time, and contain amounts of degradation product(s)within the FDA guidelines.

There is a need for stable dosage forms containing these compounds whichcomply with FDA degradation product guidelines. Applicants have nowdeveloped stable and bioavailable immediate release formulationscontaining (thio)-carbamoyl-cyclohexane derivatives. These formulationsare disclosed herein.

SUMMARY OF THE INVENTION

One embodiment of the present invention comprises(thio)-carbamoyl-cyclohexane derivatives, such ascariprazine(trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea)and pharmaceutically acceptable salts thereof, e.g., cariprazinehydrochloride that can be formulated into immediate release dosage formsin which the dosage forms have advantageous stability profiles andwherein the dosage forms preferably release the drug rapidly and arebioavailable.

In another embodiment, stable and bioavailable formulations comprisingcariprazine or pharmaceutically acceptable salts thereof are describedin which the amount of hydrolysis degradation product is less than about1% w/w.

In yet another embodiment, stable and bioavailable formulationscomprising cariprazine hydrochloride are described in which the amountof hydrolysis degradation product is less than about 1% w/w.

In additional embodiments, formulations containing from about 0.05 mg toabout 15 mg cariprazine or pharmaceutically acceptable salts thereof aredescribed wherein a single dose administration of the formulationprovides an in vivo plasma profile comprising (i) a mean C_(max) of lessthan about 26.3 ng/mL, (ii) a mean AUC_(0-∞) of more than about 2ng.hr/mL and (iii) a mean T_(max) of about 3 or more hours.

In another embodiment, a pharmaceutical formulation is describedcomprising:

(a) between about 0.5% and about 15% oftrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride,

(b) between about 5% and about 95% of lactose monohydrate,

(c) between 0% and about 10% of talc,

(d) between 0% and about 5% of colloidal silicon dioxide,

(e) between 0% and about 15% of sodium starch glycolate,

(f) between 0% and about 15% of hydroxypropyl cellulose, and

(g) between about 0.1% and about 3% of magnesium stearate.

In yet another embodiment, a pharmaceutical formulation is describedcomprising:

(a) between about 0.5% and about 15% oftrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride,

(b) between about 0.1% and about 20% of sodium carbonate,

(c) between 0% and about 10% of talc,

(d) between 0% and about 5% of colloidal silicon dioxide,

(e) between 0% and about 15% of sodium starch glycolate,

(f) between about 5% and about 95% of microcrystalline cellulose, and

(g) between about 0.1% and about 3% of magnesium stearate.

In further embodiments, formulations comprising cariprazinehydrochloride are described in which the formulation releases the activeingredient at a rate of more than about 80% within about the first 60minutes following administration of the formulation to a patient in needthereof.

In yet other embodiments, methods of treating conditions that requiremodulation of a dopamine receptor comprising administering to a patientin need thereof an effective amount of a formulation comprisingcariprazine or pharmaceutically acceptable salts thereof are describedin which the amount of hydrolysis degradation product is less than about1% w/w.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention comprisestrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the formulationcomprises less than about 1% w/wtrans-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl-amine,or a pharmaceutically acceptable salt thereof. U.S. Patent PublicationNo. 2006/0229297 discloses (thio)-carbamoyl-cyclohexane derivatives asdopamine D₃/D₂ receptor antagonists. All derivatives cited in the U.S.Publication are hereby incorporated by reference in their entirety. Oneparticular compound disclosed therein has structural formula (I):

wherein

R₁ and R₂ are each, independently, hydrogen, alkyl, alkenyl, aryl,cycloalkyl or aroyl,

or R₁ and R₂ form a heterocyclic ring with the adjacent nitrogen atom;

X is O or S;

n is 1 or 2;

and/or geometric isomers and/or stereoisomers and/or diastereomersand/or salts and/or hydrates and/or solvates thereof.

Compounds of formula (I) are orally active and very potent dopamineD₃/D₂ receptor antagonists, which bind with significantly higher potencyto D₃ than D₂ receptors.

The compounds of formula (I) have been found to be hydrolyticallyunstable. For example,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride (cariprazine hydrochloride) undergoes hydrolytic cleavageof the amide bond to formtrans-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl-aminedihydrochloride (De-BOC). Applicants have found that compounds offormula (I) undergo hydrolytic degradation when formulated with commonlyused excipients (e.g., anhydrous dicalcium phosphate, microcrystallinecellulose containing 5% water). The formation of a degradation productsuch as De-BOC in a pharmaceutical formulation is detrimental toactivity. Moreover, if the amount of degradation product exceeds FDAguidelines, additional safety and toxicology testing must be undertaken.Thus, it is important that stable and bioavailable formulationscontaining, for example, cariprazine and its salts, be developed, inwhich the amount of degradation product present falls within acceptedFDA guidelines.

The preparation of stable and bioavailable dosage forms containingcompounds of formula (I) is; however, not straightforward. For example,the use of low-moisture grade microcrystalline cellulose (e.g., AvicelPH 112), moisture absorbing/adsorbing agents (e.g., magnesium oxide) orchelating agents (e.g., ethylenediamaintetraacetic acid “EDTA”) does notprovide formulations with enhanced stability toward hydrolyticdegradation product formation.

Applicants have surprisingly found that stable and bioavailableimmediate release dosage forms comprising a compound of formula (I), ora pharmaceutically acceptable salt thereof (e.g., cariprazinehydrochloride) can be prepared. The formulations exhibit enhancedstability with respect to degradation product formation, are highlybioavailable and release the active ingredient in the stomachenvironment, e.g. at pH 1-4.

In one aspect, stable formulations of the present invention may beprepared by controlling the solid-state microenvironmental pH of theformulation. Thus, in one embodiment, the present invention relates topharmaceutical formulations (e.g., solid oral dosage forms) comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a compound that modulates the pH environment of the solidformulation (e.g., an alkaline or acidic buffering agent). Suitablebuffering agents include, for example, organic compounds (e.g.,triethylamine, arginine, diethanolamine, and meglumine), carbonates(e.g., sodium carbonate, lithium carbonate, potassium carbonate,magnesium carbonate) and bicarbonates (e.g., sodium bicarbonate, lithiumbicarbonate, potassium bicarbonate, magnesium bicarbonate). An exemplaryformulation comprises a compound of formula (I), or a pharmaceuticallyacceptable salt thereof (e.g., cariprazine hydrochloride), and sodiumcarbonate. In certain embodiments, the amount of the buffering agent(e.g., sodium carbonate) is between about 0.1% and about 50% w/w, forexample, between about 1% and about 15% w/w. Suitable ratios of thecompound of formula (I), or a pharmaceutically acceptable salt thereofto the buffering agent are, e.g., from about 1.2 to about 12.8. Incertain embodiments, the microenvironmental pH of the formulation ismore than about 6, for example, more than about 8, more than about 9,more than about 10.

Without wishing to be bound by theory, Applicants believe that raisingthe solid state microenvironmental pH of the formulation enhancesstability of the active agent toward degradation by reducing ionizationof the weakly basic drug and thereby inhibiting hydrolysis.

In another aspect, stable formulations may be prepared by formulating acompound of formula (I), or a pharmaceutically acceptable salt thereof,with an excipient having a low water activity (i.e., an excipient thathas a low amount of free water that may be released to effect hydrolyticdegradation of the active ingredient). Applicants surprisingly foundthat the total amount of water present within an excipient is not thecontrolling factor regarding hydrolytic degradation. Rather, it is theamount of water present within an excipient that is available to bereleased that is the controlling factor in reducing hydrolyticdegradation. For example, cariprazine hydrochloride formulationscontaining Avicel PH 102 (a microcrystalline cellulose containing about5% water) in the absence of a buffering agent (e.g., sodium carbonate)show substantial formation of De-Boc after storage at 1 month at 40° C.and 75% Relative Humidity (RH). In contrast, cariprazine hydrochlorideformulations containing lactose monohydrate with about 5% water shownon-detectable levels of De-Boc after storage for 6 months under similarstorage conditions.

Thus, in another embodiment, the present invention relates topharmaceutical formulations (e.g., solid oral dosage forms) comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an excipient selected from lactose monohydrate, pregelatinizedstarch (e.g., Starch 1500), mannitol, and dicalcium phosphate dihydrate.An exemplary formulation comprises a compound of formula (I), or apharmaceutically acceptable salt thereof (e.g. cariprazinehydrochloride), and lactose monohydrate. A further exemplary formulationcomprises a compound of formula (I), or a pharmaceutically acceptablesalt thereof and dicalcium phosphate dihydrate. A further exemplaryformulation comprises a compound of formula (I), or a pharmaceuticallyacceptable salt thereof and mannitol.

In certain embodiments of the compound of formula (I), when R₁ and/or R₂represent alkyl, the alkyl moiety is a substituted or unsubstitutedsaturated hydrocarbon radical which may be straight-chain orbranched-chain and contains about 1 to about 6 carbon atoms (e.g., 1 to4 carbon atoms), and is optionally substituted with one or more C₁₋₆alkoxycarbonyl, aryl (e.g., phenyl) or (C₁₋₆ alkoxycarbonyl)-C₁₋₆alkylgroups, or combinations thereof.

In additional embodiments, R₁ and R₂ form a heterocyclic ring with theadjacent nitrogen atom, which may be a saturated or unsaturated,optionally substituted, monocyclic or bicyclic ring, which may containfurther heteroatoms selected from O, N, or S. For example, theheterocyclic ring can be pyrrolidine, piperazine, piperidine ormorpholine.

In additional embodiments, when R₁ and/or R₂ represent alkenyl, thealkenyl moiety may have 2 to 7 carbon atoms and 1 to 3 double bonds.

In additional embodiments, when R₁ and/or R₂ represent aryl, the arylmoiety may be selected from an optionally substituted mono-, bi- ortricyclic aryl, such as, but not limited to, phenyl, naphthyl,fluorononyl, or anthraquinonyl group (e.g., phenyl or naphthyl). Thearyl moiety may be substituted with one or more C₁₋₆ alkoxy,trifluoro-C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkanoyl, aryl, C₁₋₆alkylthio, halogen, cyano groups or combinations thereof.

In additional embodiments, when R₁ and/or R₂ represent cycloalkyl, thecycloalkyl moiety may be selected from an optionally substituted mono-,bi- or tricyclic cycloalkyl group, such as cyclohexyl or adamantyl.

In additional embodiments, when R₁ and/or R₂ represent aroyl the arylmoiety therein is as defined above, e.g., phenyl.

In exemplary embodiments, the compound of formula (I) istrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, for example,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride

In additional embodiments, the present invention relates to formulationscomprisingtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof in which the amount ofDe-BOC present is less than about 1% w/w, such as less than about 0.5%w/w. For example, in accordance with FDA guidelines, the amount ofDe-Boc present is less than 1% w/w (for dosage forms containing up toabout 5 mg active agent), less than about 0.5% w/w (for dosage formscontaining from about 5.1 mg to about 10 mg active agent), less thanabout 0.5% w/w (for dosage forms containing from about 10.1 mg to about40 mg active agent).

Exemplary cariprazine hydrochloride formulations are set forth in Tables1 and 2.

TABLE 1 Formulations Containing Lactose Monohydrate 1^(st) Exem- plary2^(nd) Range Preferred Amount Exemplary (% Range (% Amount IngredientFunction w/w) (% w/w) w/w) (% w/w) Lactose Filler  5-95 75-95 89.0 85.9monohydrate Cariprazine Active 0.5-15  0.8-4   0.8 3.9 hydro- chlorideTalc USP Glidant  0-10 0-5 2.5 1.0 Collodial Glidant 0-5 0-2 1.0 2.5silicon dioxide Sodium starch Disintegrant  0-15 2-8 4.0 4.0 glycolateHydroxypropyl Binder  0-15 2-8 2.0 2.0 cellulose Magnesium Lubricant0.1-3.0 0.25-2.0  0.7 0.7 stearate Total (Core 100.0 100.0 100.0 100.0Tablets) Opadry Film  1-10 2-5 3.0 3.0 Coating Total (Coated 103.0 103.0Tablets)

TABLE 2 Formulations Containing Sodium Carbonate Preferred ExemplaryRange Range Amount Ingredient Function (% w/w) (% w/w) (% w/w)Microcrystalline Filler 5-95 75-95 86.2 cellulose (Avicel PH102)Cariprazine Active 0.5-15   0.8-4   0.8 hydrochloride Talc USP Glidant0-10 0-5 3.0 Collodial silicon Glidant 0-5  0-2 1.0 dioxide Sodiumstarch Disintegrant 0-15 2-8 3.0 glycolate Magnesium Binder 0.1-3.0 0.25-2.0  1.0 stearate Sodium pH Modifier 0.1-20    5-10 5.0 carbonateTotal (Core 100.0 100.0 100.0 Tablets) Opadry Film 1-10 3.0 3.0 CoatingTotal (Coated 103.0 103.0 Tablets)

The plasma concentration of the immediate release formulations of thepresent invention have a time of maximum plasma concentration (T_(max))in human patients ranging from between about 3 to about 6 hours, and anin vitro release rate of more than about 80% in about 60 minutes, morepreferably in about 30 minutes.

The pharmaceutical formulations of the present invention allow formodification of the C_(max) by changing the strength of the formulationwithout substantially affecting the T_(max) of the drug. The immediaterelease formulations described in the present invention provide thedesired T_(max) without compromising the initial peak (C_(max)).

In a further aspect, the present invention relates to a formulationcomprising from about 0.05 mg to about 15 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 26.3 ng/mL, (ii) a meanAUC_(0-∞) of more than about 2 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 22.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 3 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 0.1 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 0.2 ng/mL, (ii) a meanAUC_(0-∞) of more than about 2 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 0.2ng/mL, (ii) a mean AUC_(0-∞) of more than about 3 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 0.25 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 0.5 ng/mL, (ii) a meanAUC_(0-∞) of more than about 5 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 0.4ng/mL, (ii) a mean AUC_(0-∞) of more than about 7 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 0.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 0.9 ng/mL, (ii) a meanAUC_(0-∞) of more than about 10 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 0.8ng/mL, (ii) a mean AUC_(0-∞) of more than about 15 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 1 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 1.8 ng/mL, (ii) a meanAUC_(0-∞) of more than about 20 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 1.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 30 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 1.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 2.7 ng/mL, (ii) a meanAUC_(0-∞) of more than about 30 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 2.3ng/mL, (ii) a mean AUC_(0-∞) of more than about 45 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 2 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 3.5 ng/mL, (ii) a meanAUC_(0-∞) of more than about 40 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 3.0ng/mL, (ii) a mean AUC_(0-∞) of more than about 60 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 2.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 4.4 ng/mL, (ii) a meanAUC_(0-∞) of more than about 50 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 3.8ng/mL, (ii) a mean AUC_(0-∞) of more than about 75 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 3 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 5.3 ng/mL, (ii) a meanAUC_(0-∞) of more than about 60 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 4.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 90 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 4.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 7.9 ng/mL, (ii) a meanAUC_(0-∞) of more than about 90 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 6.8ng/mL, (ii) a mean AUC_(0-∞) of more than about 135 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 8.8 ng/mL, (ii) a meanAUC_(0-∞) of more than about 100 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 7.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 150 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 6 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 10.5 ng/mL, (ii) a meanAUC_(0-∞) of more than about 120 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 9.0ng/mL, (ii) a mean AUC_(0-∞) of more than about 180 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 7.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 13.2 ng/mL, (ii) a meanAUC_(0-∞) of more than about 150 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 11.3ng/mL, (ii) a mean AUC_(0-∞) of more than about 225 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 9 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 15.8 ng/mL, (ii) a meanAUC_(0-∞) of more than about 180 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 13.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 270 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 12.5 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 21.9 ng/mL, (ii) a meanAUC_(0-∞) of more than about 250 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 18.8ng/mL, (ii) a mean AUC_(0-∞) of more than about 375 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

In one embodiment, the formulation comprises about 15 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, wherein the single doseadministration of formulation provides an in vivo plasma profilecomprising (i) a mean C_(max) of less than about 26.3 ng/mL, (ii) a meanAUC_(0-∞) of more than about 300 ng.hr/mL and (iii) a mean T_(max) ofabout 3 or more hours. For example, the formulation provides an in vivoplasma profile comprising (i) a mean C_(max) of less than about 22.5ng/mL, (ii) a mean AUC_(0-∞) of more than about 450 ng.hr/mL and (iii) amean T_(max) of about 3 or more hours.

Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid, citric acid, formic acid, hydrobromicacid, benzoic acid, tartaric acid, fumaric acid, salicylic acid,mandelic acid, and carbonic acid. Pharmaceutically acceptable salts alsoinclude those in which the main compound functions as an acid and isreacted with an appropriate base to form, e.g., sodium, potassium,calcium, magnesium, ammonium, and choline salts. Those skilled in theart will further recognize that acid addition salts may be prepared byreaction of the compounds with the appropriate inorganic or organic acidvia any of a number of known methods. Alternatively, alkali and alkalineearth metal salts can be prepared by reacting the compounds of theinvention with the appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

For example, the pharmaceutically acceptable salt can be a hydrochloridesalt, a hydrobromide salt or a mesylate salt. In one embodiment, thepharmaceutically acceptable salt is a hydrochloride salt.

In another embodiment, the formulations of the present invention containtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride.

In yet another embodiment, the present invention relates to aformulation comprising from about 0.05 mg to about 15 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride, about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg,about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4.5 mg, about5 mg, about 6 mg, about 7.5 mg, about 9 mg, about 12.5 mg, or about 15mg. In other embodiments, the formulation is administered in an amountwhich ranges between any two of the dosage amounts.

In yet another embodiment, the present invention relates to aformulation comprising from about 0.05 mg to about 15 mgtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride wherein the single dose administration of the formulationprovides an in vivo plasma profile comprising (i) a mean C_(max) of lessthan about 26.3 ng/mL, (ii) a mean AUC_(0-∞) of more than about 2ng.hr/mL and (iii) a mean T_(max) of about 3 or more hours. For example,the formulation provides an in vivo plasma profile comprising (i) a meanC_(max) of less than about 22.5 ng/mL, (ii) a mean AUC_(0-∞) of morethan about 3 ng.hr/mL and (iii) a mean T_(max) of about 3 or more hours.

Some of the compounds useful in the formulations described herein mayexist in different polymorphic forms. As known in the art, polymorphismis an ability of a compound to crystallize as more than one distinctcrystalline or “polymorphic” species. The use of such polymorphs iswithin the scope of the present invention.

Some of the compounds useful in the formulations described herein mayexist in different solvate forms. Solvates of the compounds of theinvention may also form when solvent molecules are incorporated into thecrystalline lattice structure of the compound molecule during thecrystallization process. For example, suitable solvates includehydrates, e.g., monohydrates, dihydrates, sesquihydrates, andhemihydrates. The use of such solvates is within the scope of thepresent invention.

Dosage Forms

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

The mode of administration and dosage forms is closely related to thetherapeutic amounts of the compounds or formulations which are desirableand efficacious for the given treatment application.

Suitable dosage forms include, but are not limited to oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterilleadministration, and other dosage forms for systemic delivery of activeingredients. Formulations suitable for oral administration are preferred(e.g., tablets, capsules).

To prepare such pharmaceutical dosage forms, the active ingredient, istypically mixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration.

In preparing the formulations in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. Suitable carriers and additives include, for example, sucrose,mannitol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium lauryl sulphate, chremophor, tweens, spans,pluronics, microcrystalline cellulose, calcium phosphate, talc, fumedsilica, hydroxypropyl methyl cellulose, wax, and fatty acids, etc.

Due to their ease in administration, tablets and capsules represent themost advantageous oral dosage unit form. If desired, tablets may besugar coated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients, for example, ingredients that aidsolubility or for preservation, may be included. Injectable solutionsmay also be prepared in which case appropriate stabilizing agents may beemployed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitablefor oral administration may be presented as discrete units such ascapsules, cachets, tablets, or lozenges, each comprising a predeterminedamount of the active ingredient as a powder or granules. Optionally, asuspension in an aqueous liquor or a non-aqueous liquid may be employed,such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with, for example, a binder, disintegrant,lubricant, inert diluent, surface active agent, or discharging agent.Molded tablets comprised of a mixture of the powdered active compoundwith a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration usually comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery or delivery directly to the CNS. Administration may for examplebe intravenous, intra-arterial, intrathecal, intramuscular,subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal),etc., and may be effected by infusion pumps (external or implantable) orany other suitable means appropriate to the desired administrationmodality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders,disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

Dosages

The active ingredient present in the formulation can normally beadministered in a combined daily dosage regimen (for an adult patient)of, for example, between about 0.05 mg and about 50 mg, between about0.1 mg and about 20 mg, between about 0.1 mg and about 15 mg, betweenabout 0.1 mg and about 12.5 mg.

In certain embodiments, the pharmaceutical formulation includes about0.05 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about0.4 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.5 mg, about 2mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg,about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg,about 10.5 mg, about 11 mg, about 11.5 mg, about 12.0 mg, about 12.5 mg,about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg or about 15.0mg of active ingredient, such astrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or pharmaceutically acceptable salt thereof (e.g.,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride).

For example, the pharmaceutical formulation includes about 0.1 mg, about0.25 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5mg, about 3 mg, about 5 mg, about 6 mg, about 7.5 mg, about 9 mg, about12.5 mg or about 15.0 mg of active ingredient, such astrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or pharmaceutically acceptable salt thereof (e.g.,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,hydrochloride).

In yet further embodiments, the active ingredient (e.g.,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof), is present in theformulation in an amount which ranges between any two of these dosageamounts (e.g., between about 0.1 mg and about 15 mg, between about 0.5mg and about 12.5 mg, between about 1.5 mg and about 6 mg, between about6 mg and about 12.5 mg).

The desired dose may be administered as one or more daily sub dose(s)administered at appropriate time intervals throughout the day, oralternatively, in a single dose, for example, for morning or eveningadministration. For example, the daily dosage may be divided into one,into two, into three, or into four divided daily doses.

The duration of the treatment may be decades, years, months, weeks, ordays, as long as the benefits persist.

Methods of Treatment

The present invention further provides methods for treating conditionsthat requires modulation of a dopamine receptor, particularly, adopamine D₃ and/or D₂ receptor. In further embodiments, the presentinvention provides methods for treating a condition that requiresmodulation of a dopamine D3 and/or D₂ receptor utilizing one or moreformulations of the present invention.

Dysfunction of the dopaminergic neurotransmitter system is involved inthe pathology of several neuropsychiatric and neurodegenerativedisorders, such as schizophrenia, drug abuse and Parkinson's disease,respectively. The effect of dopamine is mediated via at least fivedistinct dopamine receptors belonging to the D₁−(D₁, D₅) or the D₂−(D₂,D₃, D₄) families. D₃ receptors have been shown to have characteristicdistribution in the cerebral dopaminergic systems. Namely, highdensities were found in certain limbic structures, such as nucleusaccumbens and islands of Calleja. Therefore, preferential targeting ofthe D₃ receptors may be a promising approach for more selectivemodulation of dopaminergic functions and consequently for successfultherapeutic intervention in several abnormalities, such asschizophrenia, emotional or cognitive dysfunctions and addiction (see,e.g., Sokoloff, P. et al.: Nature, 1990, 347, 146; Schwartz, J. C., etal.: Clin. Neuropharmacol. 1993, 16, 295; Levant, B.: Pharmacol. Rev.1997, 49, 231), addiction (see, e.g., Pilla, C. et al.: Nature 1999,400, 371) and Parkinson's disease (see, e.g., Levant, B. et al.: CNSDrugs 1999, 12, 391) or pain (see, e.g., Levant, B. et al.: Neurosci.Lett. 2001, 303, 9).

The dopamine D₂ receptors are widely distributed in the brain and areknown to be involved in numerous physiological functions andpathological states. D₂ antagonists are widely used drugs asantipsychotics, for example. However, it is also well known that massiveantagonism of the D₂ receptors leads to unwanted side-effects such asextrapyramidal motor symptoms, psychomotor sedation or cognitivedisturbances. These side effects seriously restrict the therapeuticutilization of D₂ antagonist compounds. (Wong A. H. C. et al., Neurosci.Biobehav. Rev., 27, 269, 2003)

In a further aspect, the present invention provides methods for treatingconditions which require preferential modulation of dopamine D₃ and/orD₂ receptors, for example psychoses (e.g. schizophrenia,schizo-affective disorders), cognitive impairment accompanyingschizophrenia, mild-to-moderate cognitive deficits, dementia, psychoticstates associated with dementia, psychotic depression, mania, acutemania, paranoid and delusional disorders, dyskinetic disorders such asParkinson's disease, neuroleptic induced parkinsonism, tardivedyskinesia, eating disorders (e.g. bulimia nervosa), attention deficitdisorders, hyperactivity disorders in children, depression, anxiety,sexual dysfunction, sleep disorders, emesis, aggression, autism and drugabuse, which comprises administering to a subject in need thereof aneffective amount of a compound and/or formulation of the presentinvention.

A preferred use for D₃/D₂ antagonists with D₃ preference according tothe present invention is in the treatment of schizophrenia,schizo-affective disorders, cognitive impairment accompanyingschizophrenia, mild-to-moderate cognitive deficits, dementia, psychoticstates associated with dementia, psychotic depression, mania, paranoidand delusional disorders, dyskinetic disorders such as Parkinson'sdisease, neuroleptic induced parkinsonism, depression, anxiety, drugabuse (e.g. cocaine abuse).

The particular combination of the two receptor-actions described aboveallows the simultaneous manifestation of the beneficial actions of boththe D₃ antagonism (e.g. cognitive enhancer effect, inhibition ofextrapyramidal motor symptoms, inhibitory action on drug abuse) and theD₂ antagonism (e.g. antipsychotic effect). Furthermore, the samecombination surprisingly results in canceling out the disadvantageousfeatures of D₂ antagonism (e.g. extrapyramidal symptoms, psychomotorsedation, cognitive disturbances).

In exemplary embodiments, the present invention relates to methods oftreating schizophrenia (e.g., positive symptoms of schizophrenia,negative symptoms of schizophrenia). In another embodiment, the presentinvention relates to methods of treating cognitive defects associatedwith schizophrenia.

In another embodiment, the present invention relates to methods oftreating acute mania.

In yet another embodiment, the present invention relates to methods oftreating bipolar disorder.

Definitions

The term “pharmaceutically acceptable” means biologically orpharmacologically compatible for in vivo use in animals or humans, andpreferably means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals, and more particularly inhumans.

The term “schizophrenia” is intended to include the group of mentaldisorders characterized by disruptions in thinking and perception, andincludes schizophrenia (and all its subtypes; paranoid, catatonic,disorganized, residual, undifferentiated) and other psychotic disorders(as per Diagnostic and Statistical Manual for Mental Disorders, FourthEdition, Washington, D.C. (1994): American Psychiatric Association, orThe ICD-10 Classification of Mental and Behavioural Disorders: ClinicalDescriptions and Diagnostic Guidelines, Geneva (1992): World HealthOrganization) such as schizophreniform and schizoaffective disorders,brief psychotic disorder, etc.

In a clinical evaluation, schizophrenia is commonly marked by “positivesymptoms” such as hallucinations (especially auditory hallucinationwhich are usually experienced as voices), disorganized thought processesand delusions as well as “negative symptoms” which include affectiveflattening, alogia, avolition, and anhedonia.

The term “the negative symptoms of schizophrenia” refer to a class ofsymptoms of schizophrenia which can be considered to reflect a ‘loss’ infunctional, directed thought or activity. Negative symptoms ofschizophrenia are well known in the art, and include affectiveflattening (characterized by, for example, an immobile and/orunresponsive facial expression, poor eye contact and reduced bodylanguage), alogia (‘poverty of speech’ or brief, laconic and/or emptyreplies), avolition (characterized by a reduced or absent ability toinitiate and carry out goal-directed activities), anhedonia (loss ofinterest or pleasure), asocialty (reduced social drive and interaction),apathy and other negative symptoms known to those of skill in the art.The negative symptoms of schizophrenia may be assessed using anymethodology known in the art including, but not limited to, the BriefPsychiatric Rating Scale (BPRS), and the Positive and Negative SymptomScale (PANSS). The BPRS and PANSS have subscales or factors that can beused to measure negative symptoms. Other scales have been designed toaddress specifically negative symptoms: For example the Scale for theAssessment of Negative Symptoms (SANS), the Negative Symptoms Assessment(NSA) and the Schedule for the Deficit Syndrome (SDS). Subscales of theBPRS and PANSS may also be used to assess positive symptoms, althoughmethods for specifically assessing positive symptoms are also available(e.g., the Scale for the Assessment of Positive Symptoms, or SAPS).

The terms “cognitive impairment associated with schizophrenia” and“cognitive defects associated with schizophrenia” refers to cognitivedeficits in schizophrenia patients. Cognitive impairment inschizophrenia is a core feature of the illness (i.e. not a result oftreatment or clinical symptoms). Cognitive deficits include, but are notlimited to deficits of attention/vigilance, working memory, verballearning and memory, visuospatial memory, reasoning/problem solving andsocial cognition. There are numerous neuropsychological tests used tomeasure cognitive deficits in schizophrenia, such as the Wisconsin CardSorting Test (WCST).

The terms “treat,” “treatment,” and “treating” refer to one or more ofthe following: relieving or alleviating at least one symptom of adisorder in a subject; relieving or alleviating the intensity and/orduration of a manifestation of a disorder experienced by a subject; andarresting, delaying the onset (i.e., the period prior to clinicalmanifestation of a disorder) and/or reducing the risk of developing orworsening a disorder.

An “effective amount” means the amount of a formulation according to theinvention that, when administered to a patient for treating a state,disorder or condition is sufficient to effect such treatment. The“effective amount” will vary depending on the active ingredient, thestate, disorder, or condition to be treated and its severity, and theage, weight, physical condition and responsiveness of the mammal to betreated.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical formulation that issufficient to result in a desired activity upon administration to amammal in need thereof. As used herein with respect to thepharmaceutical formulations comprisingtrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,or a pharmaceutically acceptable salt thereof, e.g.,trans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-urea,hydrochloride, the term “therapeutically effective amount/dose” refersto the amount/dose of the compound that, when combined, is sufficient toproduce an effective response upon administration to a mammal.

A subject or patient in whom administration of the therapeutic compoundis an effective therapeutic regimen for a disease or disorder ispreferably a human, but can be any animal, including a laboratory animalin the context of a trial or screening or activity experiment. Thus, ascan be readily appreciated by one of ordinary skill in the art, themethods, compounds and formulations of the present invention areparticularly suited to administration to any animal, particularly amammal, and including, but by no means limited to, humans, domesticanimals, such as feline or canine subjects, farm animals, such as butnot limited to bovine, equine, caprine, ovine, and porcine subjects,wild animals (whether in the wild or in a zoological garden), researchanimals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats,etc., avian species, such as chickens, turkeys, songbirds, etc., i.e.,for veterinary medical use.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviations,per practice in the art. Alternatively, “about” with respect to theformulations can mean plus or minus a range of up to 20%, preferably upto 10%, more preferably up to 5%.

The pharmacokinetic parameters described herein include area under theplasma concentration-time curve (AUC_(0-t) and AUC_(0-∞)), maximumplasma concentration (C_(max)), time of maximum plasma concentration(T_(max)) and terminal elimination half-life (T_(1/2)). The time ofmaximum concentration, T_(max), is determined as the time correspondingto C_(max). Area under the plasma concentration-time curve up to thetime corresponding to the last measurable concentration (AUC_(0-t)) iscalculated by numerical integration using the linear trapezoidal rule asfollows:

$\begin{matrix}{{AUC}_{0 - t} = {\sum\limits_{i = 2}^{n}{0.5 \cdot ( {C_{i} + C_{i - 1}} ) \cdot ( {t_{i} - t_{i - 1}} )}}} & {{Eq}.\mspace{14mu} 1}\end{matrix}$

where C_(i) is the plasma memantine concentrations at the correspondingsampling time point t_(i) and n is the number of time points up to andincluding the last quantifiable concentration.

The terminal half-life (T_(1/2)) is calculated using the followingequation:

$\begin{matrix}{T_{1/2} = \frac{0.693}{\lambda_{z}}} & {{Eq}.\mspace{14mu} 2}\end{matrix}$λ_(z) is the terminal elimination rate constant.

The area under the plasma concentration-time curve from time zero toinfinity is calculated according to the following equation:

$\begin{matrix}{{AUC}_{0 - \infty} = {{AUC}_{0 - t} + \frac{C_{last}}{\lambda_{z}}}} & {{Eq}.\mspace{14mu} 3}\end{matrix}$where C_(last) is the last measurable concentration.

EXAMPLES

The following examples are merely illustrative of the present inventionand should not be construed as limiting the scope of the invention inany way as many variations and equivalents that are encompassed by thepresent invention will become apparent to those skilled in the art uponreading the present disclosure.

Avicel PH102 is a microcrystalline cellulose that may be obtained fromFMC Biopolymer (Philadelphia, Pa.). Avicel PH 112 is a low moisturemicrocrystalline cellulose that may be obtained from FMC Biopolymer(Philadelphia, Pa.). Aerosil 200VV is a fumed silica that may beobtained from Evonik Industries/Degussa (Parsippany, N.J.). Prosolv SMCC90 is a microcrystalline cellulose that may be obtained from JRS Pharma(Paterson, N.Y.). Starch 1500 and Starcap 1500 are co-processed starchesthat may be obtained from Colorcon (West Point, Pa.). Starlac (a mixtureof 85% lactose monohydrate and 15% maize starch) may be obtained fromRoquette Pharma (Keokuk, Iowa). Syloid 63FP is a silica gel that may beobtained from Davison Chemical Division of W. R. Grace & Co. (Baltimore,Md.).

Dissolution rates were measured using a USP Apparatus II (paddle) with500 ml of 0.01N HCl containing 0.25% polysorbate 80.

Example 1 Preparation of a Capsule Formulations Containing CariprazineHydrochloride Example 1A

Capsules containing cariprazine hydrochloride and anhydrous calciumhydrogen phosphate were prepared according to Table 3.

TABLE 3 Composition of Capsule Formulations Amount (% w/w) Capsule ICapsule II Capsule III Ingredient (0.5 mg)* (2.5 mg)* (12.5 mg)*Cariprazine 0.5 2.7 13.6 hydrochloride Microcrystalline 59.5 58.2 51.7cellulose Calcium hydrogen 40.0 39.1 34.7 phosphate, anhydrous Total100.0 100.0 100.0 *amount of cariprazine free base

The microcrystalline cellulose (Avicel PH 102) and anhydrous calciumhydrogen phosphate were sieved together through a sieve of 0.80 mm. Thefinal powder was blended for 2 minutes in a high-shear mixer. The emptycapsule shells were filled with the powder mixture using a manualcapsule filling machine. The bulk filled capsules were then manuallypackaged into glass vials.

The stability of the capsule formulations (at 40° C. and 75% RH) isshown in Table 4.

TABLE 4 Formulation Stability Amount of De-BOC (% w/w) Time Capsule ICapsule II Capsule III Initial <0.02 <0.02 <0.02 1 Month 0.089 <0.02<0.02 2 Months 0.160 0.064 <0.02 3 Months 0.199 0.076 <0.02 6 Months NotDetermined 0.100 <0.02

High levels of an additional degradation product were observed at 3months for Capsule I.

Example 1B

Capsules containing cariprazine hydrochloride and pregelatinized starchwere prepared according to Table 5:

TABLE 5 Composition of Capsule Formulations Amount (% w/w) Capsule ICapsule II Capsule III Ingredient (0.5 mg)* (1.5 mg)* (6.0 mg)*Cariprazine 0.545 1.635 6.54 hydrochloride Pregelatinized 98.455 97.36592.46 Starch Magnesium 1.000 1.000 1.000 stearate Total 100.0 100.0100.0 *amount of cariprazine free base

The pregelatinized starch and cariprazine were sieved through a #20sieve and mixed in a V-shell blender for 20 minutes by 5 step geometricmixing using an Intensifier bar in the final step. The magnesiumstearate was sieved through #20 screen, added and the blend mixed forfurther 2 minutes. The final blend was then filled into capsules using aMG2 Futura Encapsulation machine. The capsules were packed into HDPEbottles and induction sealed.

The stability of the capsule formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 6.

TABLE 6 Formulation Stability Amount of De-BOC (% w/w) Time Capsule ICapsule II Capsule III Initial Not Detected Not Detected Not Detected 1Month Not Detected Not Detected Not Detected 2 Months 0.061 0.070 NotDetected 3 Months 0.093 0.075 Not Detected 6 Months 0.159 0.106 NotDetected Not detected means <0.05% w/w or below the limit ofquantitation.

The dissolution rates for Capsules II and III is shown in Table 7.

TABLE 7 Dissolution Rates % Dissolved Time (mins) Capsule II Capsule III0 0 0 15 97 97 20 97 98 45 95 99 60 97 99

Example 1C

Capsules containing cariprazine hydrochloride, Starlac (a combination of85% lactose monohydrate and 15% starch) were prepared according to Table8.

TABLE 8 Composition of Capsule Formulation Amount (% w/w) IngredientCapsule I (0.5 mg)* Cariprazine 0.545 hydrochloride Lactose 98.455monohydrate, starch (Starlac) Magnesium 1.000 stearate Total 100.0*amount of cariprazine free base

The Starlac and cariprazine were sieved through a #20 sieve and mixed ina V-shell blender for 20 minutes by 5 step geometric mixing using anIntensifier bar in the final step. The magnesium stearate was sievedthrough #20 screen, added and the blend mixed for further 2 minutes. Thefinal blend was then filled into capsules using a MG2 FuturaEncapsulation machine. The capsules were packed into HDPE bottles andinduction sealed.

The stability of the capsule formulations (at 40° C. and 75% RH)) in aHDPE bottle, induction sealed with no dessicant is shown in Table 9.

TABLE 9 Formulation Stability Amount of De-BOC (% w/w) Time Capsule IInitial Not Detected 2 weeks Not Detected 1 Month Not Detected 2 MonthsNot Detected 3 Months Not Detected

Example 1D

Capsules containing cariprazine hydrochloride and mannitol were preparedaccording to Table 10:

TABLE 10 Composition of Capsule Formulation Amount (% w/w) IngredientCapsule I (0.5 mg)* Cariprazine 0.545 hydrochloride Mannitol 98.455Magnesium 1.000 stearate Total 100.0 *amount of cariprazine free base

The mannitol and cariprazine were sieved through a #20 sieve and mixedin a V-shell blender for 20 minutes by 5 step geometric mixing using anIntensifier bar in the final step. The magnesium stearate was sievedthrough #20 screen, added and the blend mixed for further 2 minutes. Thefinal blend was then filled into capsules using a MG2 FuturaEncapsulation machine. The capsules were packed into HDPE bottles andinduction sealed.

The stability of the capsule formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 11.

TABLE 11 Formulation Stability Amount of De-BOC (% w/w) Time Capsule IInitial Not Detected 2 weeks Not Detected 1 Month Not Detected 2 MonthsNot Detected 3 Months 0.105

Example 1E

Capsules containing cariprazine hydrochloride and lactose monohydratewere prepared according to Table 12:

TABLE 12 Composition of Capsule Formulation Amount (% w/w) IngredientCapsule I (0.5 mg)* Cariprazine 0.545 hydrochloride Lactose 98.455monohydrate Magnesium 1.000 stearate Total 100.0 *amount of cariprazinefree base

The lactose monohydrate and cariprazine were sieved through a #20 sieveand mixed in a V-shell blender for 20 minutes by 5 step geometric mixingusing an Intensifier bar in the final step. The magnesium stearate wassieved through #20 screen, added and the blend mixed for further 2minutes. The final blend was then filled into capsules using a MG2Futura Encapsulation machine. The capsules were packed into HDPE bottlesand induction sealed.

The stability of the capsule formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 13.

TABLE 13 Formulation Stability Amount of De-BOC (% w/w) Time Capsule IInitial Not Detected 2 weeks Not Detected 1 Month Not Detected 2 MonthsNot Detected 3 Months 0.124

Example 1F

Capsules containing cariprazine hydrochloride, Starcap 1500 (a mixtureof co-processed corn starch and pregelatinized starch) were preparedaccording to Table 14:

TABLE 14 Composition of Capsule Formulation Amount (% w/w) IngredientCapsule I (0.5 mg)* Cariprazine 0.545 hydrochloride Corn starch, 98.455pregelatinized starch (Starcap 1500) Magnesium 1.000 stearate Total100.0 *amount of cariprazine free base

The Starcap1500 and cariprazine were sieved through a #20 sieve andmixed in a V-shell blender for 20 minutes by 5 step geometric mixingusing an Intensifier bar in the final step. The magnesium stearate wassieved through #20 screen, added and the blend mixed for further 2minutes. The final blend was then filled into capsules using a MG2Futura Encapsulation machine. The capsules were packed into HDPE bottlesand induction sealed.

The stability of the capsule formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 15.

TABLE 15 Formulation Stability Amount of De-BOC (% w/w) Time Capsule IInitial Not Detected 2 weeks Not Detected 1 Month Not Detected 2 Months0.08 3 Months 0.118

Example 2 Preparation of a Stable Tablet Formulations ContainingCariprazine Example 2A

Tablet formulations containing cariprazine hydrochloride and lactosemonohydrate were prepared as shown in Table 16.

TABLE 16 Tablet Formulations Amount Amount (mg/tablet) (% Tablet ITablet II Tablet III Ingredient Function w/w) 0.5 mg* 2.0 mg* 2.5 mg*Lactose Filler 88.971 62.28 249.12 311.4 monohydrate Cariprazine Active0.779 0.545 2.18 2.725 hydrochloride Talc USP Glidant 2.5 1.75 7.0 8.75Collodial Glidant 1.0 0.7 2.8 3.5 silicon dioxide Sodium starchDisintegrant 4.0 2.8 11.2 14.0 glycolate Hydroxypropyl Binder 2.0 1.45.6 7.0 cellulose Magnesium Lubricant 0.75 0.525 2.1 2.625 stearateTotal 100.00 70 280 350 *amount of cariprazine free base

All ingredients except the magnesium stearate were sieved through a #20sieve and mixed in a V-shell blender for 10 minutes. Mixing wascontinued for a further 10 minutes using an Intensifier bar in the finalstep. The magnesium stearate was sieved through #20 screen, added andthe blend mixed for further 2 minutes. The final blend was thencompressed into tablets using a Korsch PH106 compression machine. Thetablets were packed into HDPE bottles and induction sealed.

The stability of the tablet formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 17.

TABLE 17 Formulation Stability Amount of De-BOC (% w/w) Time Tablet ITablet II Tablet III Initial 0.07 Not Detected 0.06 1 Month 0.05 NotDetected Not Detected 2 Months 0.08 Not Detected 0.05 3 Months 0.06 NotDetected 0.07 6 Months 0.08 Not Detected 0.08

The dissolution rates for Tablet I after storage at 40° C. and 75% RH ina HDPE bottle, induction sealed with no dessicant is shown in Table 18.

TABLE 18 Dissolution Rates Time % Released (mins) Initial 1 Month 2Months 3 Months 6 Months 0 0 0 0 0 0 5 60 65 62 68 67 10 88 87 84 93 9815 91 89 87 96 100 30 90 90 89 97 104 45 92 91 90 98 100 60 92 91 90 98100

The dissolution rates for Tablet II after storage at 40° C. and 75% RHin a HDPE bottle, induction sealed with no dessicant is shown in Table19.

TABLE 19 Dissolution Rates Time % Released (mins) Initial 1 Month 2Months 3 Months 6 Months 0 0 0 0 0 0 15 90 89 86 92 88 30 95 94 96 96 9145 97 96 97 97 92 60 98 97 98 99 93

The dissolution rates for in Tablet III after storage at 40° C. and 75%RH in a HDPE bottle, induction sealed with no dessicant is shown inTable 20.

TABLE 20 Dissolution Rates Time % Released (mins) Initial 1 Month 2Months 3 Months 6 Months  0  0   0   0   0  0  5 64  75  68  76 77 10 86 93  89  92 90 15 91  97  93  96 94 30 97 100  97  99 95 45 98 101  98100 96 60 99 102 100 100 96

Example 2B

Tablet formulations containing cariprazine hydrochloride and lactosemonohydrate were prepared as shown in Table 21.

TABLE 21 Tablet Formulations Amount (mg/tablet) Amount Tablet I TabletII Ingredient Function (% w/w) 2.5 mg* 12.5 mg* Lactose Filler 85.85560.098 300.49 monohydrate Cariprazine Active 3.895 2.727 13.635hydrochloride Talc USP Glidant 1.0 0.7 3.5 Collodial Glidant 2.5 1.758.75 silicon dioxide Sodium starch Disintegrant 4.0 2.8 14.0 glycolateHydroxypropyl Binder 2.0 1.4 7.0 cellulose Magnesium Lubricant 0.750.525 2.625 stearate Total 100.00 70 350 *amount of cariprazine freebase

All ingredients except the magnesium stearate were sieved through a #20sieve and mixed in a V-shell blender for 10 minutes. Mixing wascontinued for a further 10 minutes using an Intensifier bar in the finalstep. The magnesium stearate was sieved through #20 screen, added andthe blend mixed for further 2 minutes. The final blend was thencompressed into tablets using a Korsch PH106 compression machine. Thetablets were packed into HDPE bottles and induction sealed.

The stability of the tablet formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 22.

TABLE 22 Formulation Stability Amount of De-BOC (% w/w) Time Tablet ITablet II Initial 0.0265 Not Detected 1 Month 0.02   Not Detected 2Months Not Detected Not Detected 3 Months Not Detected Not Detected 6Months Not Detected Not Detected

The dissolution rates for Tablet I after storage at 40° C. and 75% RH ina HDPE bottle, induction sealed with no dessicant is shown in Table 23.

TABLE 23 Dissolution Rates Time % Released (mins) Initial 1 Month 2Months 3 Months 6 Months  0   0  0  0  0   0  5  67 61 58 59 Not tested10  95 90 89 91 Not tested 15  99 95 94 95  96 30 101 97 96 96 101 45102 98 96 97 101 60 103 98 97 98 102

The dissolution rates for Tablet II after storage at 40° C. and 75% RHin a HDPE bottle, induction sealed with no dessicant is shown in Table24.

TABLE 24 Dissolution Rates Time % Released (mins) Initial 1 Month 2Months 3 Months 6 Months 0 0 0 0 0   0 5 57 68 55 57 Not tested 10 93 8983 86 Not tested 15 101 93 91 92  97 30 105 97 96 96 101 45 107 98 98 97101 60 108 99 99 98 102

Example 2C

Tablets containing cariprazine hydrochloride and sodium carbonate as abuffering agent were prepared according to Table 25:

TABLE 25 Tablet Formulations Amount Ingredient Function (% w/w)Microcrystalline Filler 86.221 cellulose (Avicel PH102) CariprazineActive 0.779 hydrochloride Talc USP Glidant 3.000 Collodial siliconGlidant 1.000 dioxide Sodium starch Disintegrant 3.000 glycolateMagnesium Lubricant 1.000 stearate Sodium pH modifier 5.000 carbonateTotal 100.000

All ingredients except the magnesium stearate were sieved through a #20sieve and mixed in a V-shell blender for 15 minutes. The magnesiumstearate was sieved through #20 screen, added and the blend mixed forfurther 2 minutes. The final blend was then compressed into tabletsusing a Korsch PH106 compression machine. The tablets were packed intoHDPE bottles and induction sealed.

The stability of the tablet formulations (at 40° C. and 75% RH) in aHDPE bottle, induction sealed with no dessicant is shown in Table 26.

TABLE 26 Formulation Stability Amount of De-BOC Time (% w/w) Initial NotDetected 2 Weeks Not Detected 1 Month 0.090 2 Months 0.102 3 Months0.176 6 Months 0.165

The amount of De-BOC present in formulations containing differingamounts of sodium carbonate (stored for 3 months at 40° C., 75% RH insealed 60 cc HDPE bottles with no desiccant) is shown in Table 27.Slurries were prepared by taking a tablet and dispersing it in thecorrect volume of deionized water needed to prepare a suspensioncontaining 2% solids. The pH of the slurry was then measured using pHmeter.

TABLE 27 Formulation Stability Amount of De-Boc after Amount of Sodium 3months at Carbonate pH 40 C./75% RH (% w/w) (2% slurry) (% w/w) 1.0 10.40.36 5.0 10.9 0.17 10.0 11.1 0.14

Example 3 Comparison Examples

Additional tablets containing cariprazine hydrochloride and otherexcipients were prepared according to Table 28:

TABLE 28 Tablet Formulations Ingredient Tablet Tablet (% w/w) Tablet 1Tablet 2 Tablet 3 Tablet 4 Tablet 5 Tablet 6 Tablet 7 Tablet 8 Tablet 910 11 Cariprazine 0.779 0.779 0.779 0.779 0.779 0.779 0.779 0.779 0.7790.779 0.779 hydrochloride Talc USP 3.000 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.03.0 3.0 Sodium starch 5.000 5.0 0.5 0.5 3.0 0.5 3.0 0.5 0.5 3.0 3.0glycolate Magnesium stearate 1.000 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.01.0 Aerosil 200VV 0.700 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 ProsolvSMCC90 89.521 — — — — — — — — — Avicel PH102 — 89.221 62.721 62.72181.221 93.721 88.721 — — 91.121 91.201 Starch 1500 — — 31 — — — — 93.721— — Dicalcium — — — 31.0 — — — — — — — phosphate dihydrate Magnesiumoxide — — — — 10.0 — — — — — — Syloid 63FP — — — — — — 2.5 — — — —Butylated — — — — — — — — — — 0.01 Hydroxyanisol Butylated — — — — — — —— — — 0.01 Hydroxytoluene EDTA — — — — — — — — — 0.1 — Avicel PH112 — —— — — — — 93.721 — — — (Low Moisture) Total 100 100 100 100 100 100 100100 100 100 100

All ingredients except the magnesium stearate were sieved through a #20sieve and mixed in a V-shell blender for 15 minutes. The magnesiumstearate was sieved through #20 screen, added and the blend mixed forfurther 2 minutes. The final blend was then compressed into tabletsusing a Korsch PH106 compression machine. The tablets were packed intoHDPE bottles and induction sealed.

The stability of the tablet formulations described in Table 29 (storedat 40° C. and 75% RH in 60 cc HDPE bottles, induction sealed with nodessicant) is shown in Table 29.

TABLE 29 Formulation Stability Amount of De-BOC (% w/w) Tablet TabletTime Tablet 1 Tablet 2 Tablet 3 Tablet 4 Tablet 5 Tablet 6 Tablet 7Tablet 8 Tablet 9 10 11 Initial 0.058 0.052 ND ND ND ND ND ND ND ND ND 2Weeks 0.344 0.273 0.119 0.194 0.136 0.196 0.069 0.102 0.076 0.095 0.0931 Month 0.617 0.483 0.192 0.342 0.350 0.749 0.139 0.369 0.36  0.2450.226 2 Months 1.318 0.925 0.720 0.799 0.464 1.411 0.312 0.512 0.4960.500 0.474 3 Months 2.66  1.765 Not Not Not Not Not 0.755 0.760 Not NotTested Tested Tested Tested Tested Tested Tested

As can be seen from Table 30, the amount of De-Boc present in each ofthese tablet formulations at 2 months is greater than for the capsuleand tablet formulations of the present invention described in Examples 1and 2.

Example 4 A Double-Blind Placebo Controlled Single Dose Study Conductedin Healthy Male Volunteers

A double-blind, placebo controlled single dose study of thepharmacokinetic parameters of cariprazine (capsules) in healthy malevolunteers was conducted. The design of the study is shown in Table 30.

TABLE 30 Study Design Number of Wash-Out Subjects Interval ReceivingDose Before PK Blood Group Active Drug Period (mg) Condition Period 2Sampling I 6 1 1 Fasted 0-168 h II 6 1 2.5 Fasted 0-336 h I 6 2 2 Fasted~2 weeks 0-672 h II 6 2 1.5 Fasted ~4 weeks 0-336 h III 6 1 0.5 Fasted0-168 h

The composition of the capsules is given below in Table 31.

TABLE 31 Capsule Composition Amount (mg) 0.5 mg 2.5 mg 12.5 mgIngredient Capsule Capsule Capsule Cariprazine 0.543 2.713 13.563hydrochloride Microcrystalline 59.457 58.177 51.690 cellulose Calcium40.00 39.110 34.747 hydrogen phosphate, anhydrous

The mean pharmacokinetic parameters observed after administration of asingle dose of 0.5 to 2.5 mg cariprazine are shown below in Table 32.

TABLE 32 Mean Pharmacokinetic Parameters Treatment Dose C_(max,)AUC₀₋₁₆₈, T_(max,) T_(1/2) Group Period (mg) (ng/mL) (ng/mL * h) (h) (h)III 1 0.5 0.14 14.09 6 216.7 I 1 1 0.76 35.36 3 185.3 II 2 1.5 1.1946.66 3 129.9 I 2 2 2.53 95.33 3 130.0 II 1 2.5 2.50 97.46 4 138.5

Mean maximum plasma concentrations (C_(max)) were generally obtainedwithin about 3 to about 6 hours of dosing. T_(max) values are about 3 toabout 6 hours.

The pharmacokinetics oftrans-1{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-3,3-dimethyl-ureahydrochloride over the single-dose range of 0.5 mg to 2.5 mg suggestapproximate dose proportionality of exposure relative to mean AUC.Linear calculated pharmacokinetic parameters (based on the 2.0 mg data(Table 35, 80% of AUClast, Treatment I) for dosages greater than 2.0 mgand on the 0.5 mg data for dosages lower than 0.5 mg (Table 33) areshown in Table 33.

TABLE 33 Linear Calculated Pharmacokinetic Parameters Mean C_(max) MeanAUC₀₋₁₆₈ Dose (mg) (ng/mL) (ng/mL * h) 0.1 0.03 2.82 0.25 0.09 1.05 33.80 96.8 4.5 5.70 145.2 5 6.33 161.4 6 7.60 193.6 7.5 9.50 242.1 911.39 290.4 12.5 15.83 403.5 15 18.99 484.2One skilled in the art with the benefit of this disclosure may readilydetermine pharmacokinetic parameters for any specific dosage ofcariprazine used in a formulation.

Example 5 A Single-Center, Randomized, Open-Label, Parallel-GroupSingle-Dose Study

The objectives of this study were (i) to assess the effect of food onthe oral bioavailability of cariprazine (2-mg tablet), (ii) to assessthe effect of gender on the oral bioavailability of cariprazine after asingle oral dose (2-mg tablet), and (iii) to evaluate thepharmacokinetics of cariprazine and its metabolites after an oral dose(2-mg tablet).

Methodology

This clinical study was conducted as a single-center, randomized,open-label, parallel-group single-dose study. A total of 42 healthy maleand female patients aged 18-45 years were selected, with an approximatemale-to-female ratio of 1:1.

Dosing occurred in two treatment sessions (Treatment 1 and Treatment 2)separated by 5 to 7 days. The subjects were randomized with 1:1male-female ratio to receive one of the following two treatments:

-   Treatment 1: Single oral dose of one 2-mg cariprazine tablet under    fasted conditions (12 female, 11 male subjects)-   Treatment 2: Single oral dose of one 2-mg cariprazine tablet under    fed conditions (10 female, 9 male subjects)

Subjects were given the study drug with 240 mL of water in the clinicunder fed/fasted conditions at 0800 hours on Day 1. Subjects takingTreatment 1 underwent a 10-hour overnight fast before dosing on Day 1and continued fasting for an additional 4 hours postdose. Subjectstaking Treatment 2 underwent a 10-hour overnight fast before eating a USFood and Drug Administration standardized high-fat breakfast at 0730hours on Dosing Day 1.

This study was 30 days in duration (Day-1 through the lastpharmacokinetic (PK) blood sample collection on Day 29).

Patient Evaluations

Vital Signs/Adverse Event Assessment

Heart rate and blood pressure were measure in the supine position (thesubject lying down for at least 5 minutes prior to testing) on the samearm throughout the study and before any corresponding blood sample wascollected. In addition to the Screening and End-of-Study measurements,vital signs (BP and pulse) were measured at:

Day 1: (0.0 (predose), 2, 4, 8 and 12 hours postdose)

Day 2: 25 hours after Day 1 dose administration

Day 3: 48 hours after Day 1 dose administration

Day 5: 96 hours after Day 1 dose administration

Blood Sampling

Blood sampling was performed at the following times to determinecariprazine plasma concentrations:

0.0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 168, 336,504 and 672 hours postdose.

The mean pharmacokinetic parameters observed during the study arepresented in Table 34.

TABLE 34 Mean Pharmacokinetic Parameters Treatment C_(max) AUC_(last)AUC_(∞-obs) Group (ng/mL) (ng · h/mL) (ng · h/mL) Tmax (h) T½ (h)Treatment 1 1.99 80.69 89.87 4.91 202.60 (Fasted) Treatment 1 1.72 89.2296.96 9.21 198.33 (Fed)

Example 6 A Multiple Dose Study Conducted in Healthy Male Volunteers

Thirty-two healthy male subjects (mean age=24.9 years) were randomizedinto 4 groups (I-IV). In each group, 2 subjects received placebo and 6subjects received one of the following treatments:

-   -   (I) 7 doses of 0.5 mg cariprazine administered every other day;    -   (II) 14 doses of 0.5 mg cariprazine every day;    -   (III) 2 doses of 0.5 mg cariprazine followed by 12 doses of 1.0        mg cariprazine every day; and    -   (IV) 21 doses of 1.0 mg cariprazine every day.

Plasma samples were analyzed for cariprazine by a validated LC-MS/MSassay (Internal Standards: deuterated compounds; Sample preparation:Liquid-liquid extraction after alkalization; Sample Volume: 1 mL;Calibration Range: 0.05-25 ng/mL; Ionization: +ESI with MRM mode).

The design of the study is shown below in Table 35.

TABLE 35 Study Design Number of PK Blood Sampling Subjects PK Profile PKProfile Receiving After After Active Frequency Dose, First Predose LastGroup Drug of dosing mg Days Condition Dose Samples Dose I 6 once every0.5 1, 3, 5, 7, Fasted 0-48 h Days 3, 5, 0-3 other day 9, 11, 13 7, 9,11 weeks II 6 once daily 0.5 1-14 Fasted 0-24 h Days 2, 3, 0-9 4, 5,weeks 7, 9, 11, 13 III 6 once daily 0.5/1 1-2 (0.5 mg) Fasted 0-24 hDays 2, 3, 0-9 3-14 (1 mg) 4, 5, weeks 7, 9, 11, 13 IV 6 once daily 11-21 Fasted 0-24 h Days 2, 3, 0-9 5, 8, 11, 14, weeks 16, 18, 19, 20The mean pharmacokinetic parameters observed are shown below in Table36.

TABLE 36 Mean Pharmacokinetic Parameters Treatment C_(max) AUC_(0-τ),Group ng/mL t_(max), h ng/mL * h I 1.034 4 32.9 (22.3) (3-6) (21.6) II1.418 3.5 25.0 (18.0) (2-4) (22.8) III 3.193 4 53.6 (25.9) (2-4) (30.6)IV 3.897 56.8 (18.9) (2-3) (18.1)

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims. It is further to be understood that allvalues are approximate, and are provided for description.

We claim:
 1. A method of treating a condition selected from the groupconsisting of schizophrenia, bipolar disorder, acute mania, anddepression comprising administering to a patient in need thereof a solidoral dosage form comprising between about 0.5% and about 15% ofcariprazine or a pharmaceutically acceptable salt thereof, an excipienthaving low water activity selected from the group consisting of and apregelatinized starch, mannitol, anhydrous calcium hydrogen phosphate,and mixtures thereof, and between about 0.1% and about 0.5% oftrans-4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl-amineor a pharmaceutically acceptable salt thereof; wherein the formulationhas a pH in the range of about 9.0 to about 12.0.
 2. The method of claim1, wherein the solid oral dosage form comprises cariprazine or apharmaceutically acceptable salt thereof in an amount from about 0.5 mgto about 15 mg.
 3. The method of claim 1, wherein the solid oral dosageform comprises cariprazine or a pharmaceutically acceptable salt thereofin an amount from about 1 mg to about 12 mg.
 4. The method of claim 1,wherein the solid oral dosage form comprises magnesium stearate.
 5. Themethod of claim 1, wherein the excipient having a low water activitypregelatinized starch is present in an amount greater than 80% by weightof the solid oral dosage form.
 6. The method of claim 1, wherein thesolid oral dosage form comprises a compound that modulates the pHenvironment of the composition solid oral dosage form in an amountbetween about 1% by weight and 15% by weight of the composition solidoral dosage form.
 7. The method of claim 1, wherein the solid oraldosage form has a dissolution rate of more than about 80% within aboutthe first 60 minutes following administration of the solid oral dosageform to the patient.
 8. The method of claim 1, wherein the excipientcomprises pregelatinized starch.
 9. The method of claim 1, wherein theexcipient comprises mannitol.
 10. The method of claim 1, wherein theexcipient comprises anhydrous calcium hydrogen phosphate.